SUMMARY This application is being submitted in response to NOT-TR-18-019. Our goal is to use the existing dataset of patients enrolled in the Natural History Study of the Synucleinopathies, Project 1 of the Autonomic Rare Diseases Consortium, to explore the potential contribution of supine hypertension to the morbidity and mortality of patients with synucleinopathies. Our ultimate goal is to improve survival of patients with synucleinopathies, which are progressive neurodegenerative disorders caused by the abnormal accumulation of misfolded ?- synuclein (?Syn) in the nervous system. Neurodegeneration of the autonomic nervous system causing cardiovascular autonomic dysfunction is a characteristic feature of patients with synucleinopathies. While a sustained fall in blood pressure on standing (i.e., neurogenic orthostatic hypotension, nOH) is their most commonly recognized feature, approximately 50% of patients with autonomic failure also have hypertension in the supine position. Because nOH and supine hypertension occur concomitantly in the same patient, their consequences are difficult to disentangle. nOH has immediate, short-term consequences such as syncope and falls, but it has also been associated with long-term renal, cardiac, and cerebrovascular complications was well as premature death. However, these studies did not account for the presence of supine hypertension as a potential confounder and hypertension is strongly associated with renal, cardiac and cerebral damage, as well as increased mortality. Therefore, the extent to which the results of previous studies of patients with hypertension apply to those with supine hypertension and nOH is unclear. Our HYPOTHESIS is that supine hypertension in patients with autonomic synucleinopathies increases the risk of end-target organ damage and negatively impacts survival in these patients. Our OBJECTIVE is use the existing dataset of patients enrolled in the Natural History Study of the Synucleinopathies (Project 1 of the Autonomic Rare Diseases Consortium) to determine whether supine hypertension contributes to morbidity and premature mortality of patients with synucleinopathies. Our AIMS are: ONE. To determine if supine hypertension is associated with increased burden of end-target organ damage in patients with synucleinopathies. And TWO: To define if supine hypertension increases the risk of major cardiovascular events and mortality in patients with synucleinopathies. It is conceivable that excess mortality in patients with synucleinopathies is not only due to the neurodegenerative process but, perhaps, also due to supine hypertension. If our hypothesis results to be correct, implementation of clinical studies for the prevention and treatment of supine hypertension in patients with synucleinopathies will be warranted.